This invention relates to a process for the preparation of N-benzyl indoles, and to intermediates for use in the 5 process, and to certain substantially optically pure N-benzyl indoles obtained by the process.
EP-A-0469833 discloses a class of N-benzyl indoles including compounds of the formula 
in which R1 is hydrogen, halo, C1-4 alkyl, C1-4 alkoxy, nitrile, optionally protected carboxy, optionally protected tetrazolyl, trihalomethyl, hydroxy-C1-4 alkyl, aldehyde, xe2x80x94CH2Z, xe2x80x94CHxe2x95x90CHxe2x80x94Z or xe2x80x94CH2CH2Z where Z is optionally protected carboxy or optionally protected tetrazolyl; R2 is halo, nitrile, an optionally protected acid group or xe2x80x94CONR7R8 where R7 and R8 are hydrogen or C1-4 alkyl; R4 is C2-4 alkyl, or C2-4 alkyl substituted by xe2x80x94CONR7R8 or an optionally protected acid group; R5 is 
where W is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, R9 is hydrogen, halo, C1-4 alkyl, C1-4 alkoxy or trihalomethyl, and R10 is hydrogen, C1-4 alkyl, C3-6 alkenyl, C3-6 cycloalkyl or C1-4 alkyl-C3-6 cycloalkyl; R6 is hydrogen or C1-4 alkyl; X is xe2x80x94Oxe2x80x94(CH2)nCR11R12xe2x80x94, xe2x80x94CR11R12xe2x80x94, xe2x80x94CR11R12.(CH2)nxe2x80x94CR13R14xe2x80x94 or xe2x80x94CR11xe2x95x90CR12xe2x80x94 where R11, R12, R13 and R14 are each hydrogen or C1-4 alkyl, and n is 0, 1 or 2; and Y is xe2x80x94Oxe2x80x94CR15R16xe2x80x94, xe2x80x94CR15xe2x95x90CR16xe2x80x94 or xe2x80x94CR15R16. CR17R18xe2x80x94 where R15, R16, R17 and R18 are each hydrogen or C1-4 alkyl; and salts thereof.
Amongst the compounds disclosed in EP-A-0469833, one particularly important compound has the formula 
The compounds disclosed in EP-A-0469883 are leukotriene antagonists, and are accordingly indicated for therapeutic use in the treatment of diseases in which leukotrienes are implicated. These include allergic reactions of the pulmonary system in which leukotrienes are thought to be causal mediators of bronchospasm, for example, in allergic lung disorders such as extrinsic asthma and industrial asthmas such as Farmers Lung, and in other inflanmmatory disorders, for example, associated with acute or chronic infectious diseases such as allergic skin diseases, ectopic and atopic eczemas, psoriasis, contact hypersensitivity and angioneurotic oedema, bronchitis and cystic fibrosis and rheumatic fever. The compounds disclosed in EP-A-0469833 also have potential in the treatment of vascular diseases such as shock and ischaemic heart diseases for example coronary artery disease and myocardial infarction, cerebrovascular diseases, and renal diseases such as renal ischaemia.
EP-A-0469833 discloses certain processes for the preparation of the N-benzyl indoles disclosed therein. However, the overall yield which is obtainable using the processes disclosed in EP-A-0469833 is not high, and the compounds are generally obtained in the form of racemates. In many cases, including the case of the compound of Formula (Ixe2x80x2) above, separation of enantiomers by conventional techniques, such as by reaction with a chiral amine followed by fractional recrystallisation, or separation on a chiral chromatographic support has been found to be extremely difficult. Nevertheless it has now been found that the S-enantiomer of the above compound of Formula (Ixe2x80x2) is preferred and pharmacologically superior.
It is accordingly an object of the present invention to provide an improved process for preparing the N-benzyl indoles described above. It is a further object of the invention to provide a process for preparing such N-benzyl indoles in the form of their substantially pure enantiomers.
According to one aspect of the present invention, there is provided a process which comprises the step of reacting an indoline compound of the formula 
with epoxide compound of the formula 
to form a compound of the formula 
wherein R2a is selected from the groups recited above for R2, or R2axe2x80x94Xxe2x80x94 is a protected hydroxyl group, and wherein Zxe2x80x2 is a group of formula xe2x80x94Yxe2x80x94R5 as defined herein, or Zxe2x80x2 is a substituent that can be converted into a group of formula xe2x80x94Yxe2x80x94R5. In any event, the group W must be chemically stable during the above-described reaction between compounds of formulae (II) and (III). Since the linking group Y is preferably a vinyl group xe2x80x94CR15xe2x95x90CR15xe2x95x90CR16xe2x80x94, the substituent Zxe2x80x2 is preferably a group that can be converted into a vinyl group by an olefination reaction. The preferred olefination method is palladium salt catalyzed Heck coupling, as described further below, and accordingly Zxe2x80x2 is preferably a leaving group such as Cl, Br, I, or a sulfonate such as trifluoromethylsulfonate or tosylate. The most preferred substituent Zxe2x80x2 in this case is Br. Other preferred olefinations include Wittig reactions, in which case the substituent Zxe2x80x2 is preferably xe2x80x94CHO, or protected xe2x80x94CHO, such as an acetal.
The reaction is carried out in a suitable solvent such as dry acetonitrile, and is preferably conducted in the presence of a Lewis acid catalyst such as magnesium perchlorate.
In the above formula (I), a halo substituent can be for example, chloro, bromo and fluoro and is preferably chloro. A C1-4 alkyl group includes methyl, ethyl, propyl, isopropyl, butyl and tert butyl and is preferably methyl or ethyl, and a C1-4 alkoxy group is one such alkyl group attached through oxygen. A hydroxy C1-4 alkyl group is a hydroxy-substituted C1-4 alkyl group preferably of the formula HO(CH2)nxe2x80x94 where n is 1 to 4, a preferred example being hydroxymethyl. A C3-6 cycloalkyl group includes for example cyclopropyl, cyclopentyl and cyclohexyl, and is preferably cyclopropyl. The C3-6 cycloalkyl group can be substituted by a C1-4 alkyl. A C2-6 alkenyl group is preferably propenyl or isopropenyl. A trihalomethyl group is preferably trifluoromethyl. An optionally substituted phenyl group is phenyl itself, or phenyl substituted with one or more, preferably 1 to 3, substituents selected from C1-4 alkyl, especially methyl, C1-4 alkoxy, especially methoxy and ethoxy, hydroxy, nitro, cyano, halo, especially chloro or fluoro, trihalomethyl, especially trifluoromethyl, carboxy C1-4 alkoxy-carbonyl, and optionally protected tetrazolyl.
An acid group can be any acid group conventionally used in pharmaceutical chemistry and the term includes, for example tetrazolyl (1H-tetrazol-5-yl), carboxy (xe2x80x94COOH), phosphonate (xe2x80x94PO(OH)2), sulphonate (xe2x80x94SO2OH), acyl sulphonamido (xe2x80x94CONHSO2R, where R is preferably C1-4 alkyl or optionally substituted phenyl) or cyanoguanidinyl (xe2x80x94NHC (NH2)xe2x95x90NCN). Especially preferred examples are tetrazolyl and carboxy.
When R5 is the group 
it comprises groups of the following type 
and the quinolin-2-yl group is the most preferred.
R1 is preferably hydrogen or halogen, and especially hydrogen, and when it is other than hydrogen it is preferably attached to the indole nucleus at the 4-position.
The group R2xe2x80x94Xxe2x80x94 is attached to the indole nucleus at the 6- or 7-position, and when X is xe2x80x94Oxe2x80x94(CH2)nCR11CR12xe2x80x94 via the oxygen atom. R2 is preferably an acid group especially tetrazolyl or carboxyl.
The R5 group is preferably quinolin-2-yl where the substituent R9, which is preferably hydrogen or halo, is attached at the 7-position. The group R5xe2x80x94Yxe2x80x94 can be attached with the 2-, 3- or 4-positions to the phenyl nucleus, and when R is xe2x80x94Oxe2x80x94CR15R16xe2x80x94 via the oxygen atom. R5xe2x80x94Yxe2x80x94 is preferably attached at the 3-position.
The R6 group is preferably hydrogen and when it is C1-4 alkyl is preferably attached at the 3-position.
The linking group X is preferably xe2x80x94Oxe2x80x94CR11R12xe2x80x94 or CR11R12.CR13R14xe2x80x94, and R11, R12, R13 and R14 are preferably hydrogen. Linking group Y is preferably of the formula xe2x80x94Oxe2x80x94CR15R16, or xe2x80x94CR15xe2x95x90CR16xe2x80x94, and R15, R16, R17, and R18 are preferably hydrogen.
When acid substituents on the compound of formula (I) require protection during preparation they may be protected by conventional protecting groups. Such protected compounds are included in the scope of the invention, though the preferred compounds with optimum biological properties are the unprotected compounds derived from them. A carboxy can be protected by protecting groups which include the well known ester forming groups used for the temporary protection of acidic carboxylic acid groups. Examples of such groups which have general use are readily hydrolysable groups such as arylmethyl groups, haloalkyl groups, trialkylsilyl groups, alkyl groups, and alkenyl groups. A preferred protected carboxy is C1-4 alkoxy-carbonyl. Other carboxy protecting groups are described by E. Haslam in Protective Groups in Organic Chemistry. Such protecting groups are also suitable for protecting phosphonate and sulphonate substituents. Furthermore, it is usually necessary to protect any tetrazolyl group during the process of preparation, and suitable and well known protecting groups for this purpose include groups of the formula xe2x80x94CRxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are hydrogen, C1-4 alkyl or phenyl optionally substituted by one or more electron-donating groups such as, for example, C1-4 alkoxy, and Rxe2x80x2xe2x80x3 is phenyl optionally substituted by one or more electron donating groups. Preferred examples include trityl and benzhydryl.
When the acid substituent is tetrazolyl, then most preferred methods involve carrying out the earlier reaction steps on precursor nitrile compounds, and then converting the nitrile groups into tetrazolyl by reaction with an azide at or near the last step of the synthesis.
It is believed that all of the other substituents defined herein for compounds of formula (I) may be present when compound (II) is reacted with compound (III) in accordance with the present invention, and the substituents should not substantially interfere with this reaction step. It will be recognized that side reactions may occur with certain substituents in certain of the other reaction steps in the preferred total synthesis route described herein. The person skilled in the art will recognize where side reactions could occur and avoid the side reactions by means of suitable protecting groups, or the like.
The compounds of Formula IV as defined above form a further aspect of the present invention.
Preferably, the process according to the present invention further comprises the step of converting the compound of formula IV into a compound of formula (IVa) 
where R4a is C2-4 alkyl or C2-4 alkyl substituted by cyano, hydroxy, xe2x80x94CONR7R8, or an optionally protected acid group.
For example, the present invention preferably provides a process as above for preparing a compound of formula (I), further including the step of converting the compound of formula (IV) to the olefin 
The compound of formula (IV) may be converted into the olefin via the thiocarbonate (Va) 
using the Corey-Winter olefination method. For example, 1,1xe2x80x2-thiocarbonyldiimidazole and 4-dimethylaminopyridine in dichloromethane may be used to obtain the thiocarbonate, and a trivalent phosphorus reagent such as 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine is then used to convert the thiocarbonate to the olefin. This reaction is preferably carried out in a solvent such as THF.
The olefin of Formula (V), in turn, is preferably converted to the corresponding alcohol (VI) 
by a hydroboration-oxidation sequence, such as heating with borane-tetrahydrofuran complex (BH3xe2x80x94THF) in tetrahydrofuran, followed by the addition of water, alkali metal hydroxide i and hydrogen peroxide.
Preferably, the method of the present invention then includes the step of oxidising the above indoline alcohol compound to the corresponding indole compound of the formula 
Such oxidation may conveniently be achieved by reaction with chlorotrimethylsilane and triethylamine in dichloromethane, followed by treatment with a mild oxidizing agent, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
Preferably, the indole alcohol of formula (VII) is then converted into a compound of formula (IVa) 
This step is preferably carried out by: (i) converting the hydroxyl group into an anionic leaving group, e.g. converting the hydroxyl group into trifluoromethylsulfonate by treatment with trifluoromethylsulfonic anhydride and mild base, followed by (ii) reaction with a suitable nucleophile to produce the desired group R4a, e.g. reaction with cyanide ion, or cyanomethylation with NCCH2CO2H and lithium diisopropylamide, or with CH3CN and lithium diisopropylamide in aprotic solvent.
When R2axe2x80x94Xxe2x80x94 is a protected hydroxy group, the process according to the invention may further comprise the step of removing the protecting group R2a from the compound of formula (VII) and then reacting the deprotected compound with a compound of the formula Brxe2x80x94(CH2)nCR11R12xe2x80x94R2, wherein n, R11 and R12 are as defined above, to form a compound of the formula 
The protecting group R2a may conveniently be removed using a conventional O-dealkylating agent, such as boron tribromide in a solvent such as dichloromethane.
In preferred embodiments, the present invention provides a process for preparing a compound of formula (I), wherein Y is xe2x80x94CR15xe2x95x90CR16xe2x80x94, comprising the step of reacting the compound of formula (IVa) wherein Zxe2x80x2 is an anionic leaving group, preferably Br, with a compound of the formula CHR15xe2x95x90CR16xe2x80x94R5 in a Heck coupling reaction to form a compound of the formula 
The Heck coupling reaction requires the presence of a palladium salt as catalyst, a polar solvent, a base, and a monodentate or bidentate phosphine ligand. For example, the reaction preferably uses bisdiphenylphosphinopropane, palladium dichloride in acetonitrile and triethylamine. It has been found that, for compounds of formula VIII, the reaction can be carried out in a sealed bottle at a temperature of 90xc2x0 to 100xc2x0 C.
When R2a in formula (IX) is cyano and/or R4a is cyano-C2-4 alkyl, the compound of formula (IX) may be reacted with an azide, such as Bu3SnN3, to convert the cyano groups to tetrazolyl groups.
Preferably, the compound of formula (III) is formed by epoxidation of a compound of the formula 
The epoxidation is preferably a Sharpless asymmetric epoxidation, as described in U.S. Pat. No. 4,471,130 or U.S. Pat. No. 4,900,847, the entire disclosure of which is incorporated herein by reference. This epoxidation is carried out with a titanium alkoxide, an organic hydroperoxide, and a chiral glycol in an inert aprotic solvent. Preferred reagents are Ti(OiPr)4, t-BuOOH and diethyl tartrate. If the diethyl tartrate is the L-(+)-isomer, then the resulting compound of formula (III) has the structure 
and the resulting compound of formula (I) has the structure 
On the other hand, if the diethyl tartrate is the D-(xe2x88x92)-isomer, then the resulting compound of formula (III) has the structure 
and the resulting compound of formula (I) has the structure 
Accordingly, the present invention also provides compositions comprising a compound of formula 
substantially free of the enantiomer 
as well as compositions comprising a compound of formula (Ib) substantially free of the enantiomer (Ia). The enantiomeric ratio in such compositions is preferably at least 80:10, and more preferably at least 90:10. In many cases, an enantiomeric ratio greater than 95:5 is obtained.